Novel Detox Gel Depot Sequesters β-Amyloid Peptides in a Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's Disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39-43 amino acid peptide (amyloid β or Aβ) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that interfere with Aβ-Aβ interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids 16-20) region in the Aβ molecule have been investigated as possible drug candidates. Retro-inverso (RI) peptide of this pentapeptide, ffvlk, has been shown to bind artificial fibrils made from Aβ with moderate affinity. We hypothesized that a 'detox gel', which is synthesized by covalently linking a tetrameric version of RI peptide ffvlk to poly (ethylene glycol) polymer chains will act like a 'sink' to capture Aβ peptides from the surrounding environment. We previously demonstrated that this hypothesis works in an in vitro system. The present study extended this hypothesis to an in vivo mouse model of Alzheimer's Disease and determined the therapeutic effect of our detox gel. We injected detox gel subcutaneously to AD model mice and analyzed brain levels of Aβ-42 and improvement in memory parameters. The results showed a reduction of brain amyloid burden in detox gel treated mice. Memory parameters in the treated mice improved. No undesirable immune response was observed. The data strongly suggest that our detox gel can be used as an effective therapy to deplete brain Aβ levels. Considering recent abandonment of failed antibody based therapies, our detox gel appears to have the advantage of being a non-immune based therapy.